Clinical Aspects of the CCM1 Common Mutation

Connie Lee, Psy.D.President and CEOAngioma Alliance

The Baca Family Historical Project

Genetics of the Common CCM1 Mutation23 pairs of

Chromosomes

One from each parent

Common Hispanic Mutation is on one

copy of chromosome 7

Losing the KRIT1 Protein

• There are many places in the body where KRIT1 plays minor or no role.

• But in capillary blood vessels in brain and spinal cord, it keeps junctions tight between endothelial cells.

• Without KRIT1, cavernous angiomas (cavernous malformation, cavernoma) form.

• Mulberry-shaped, thin-walled, leaky malformations. Slow blood flow.

Symptoms that lead to diagnosis

Seizure – 50%

Hemorrhage – 25%

Focal Neurological Deficit – 25%

More than 20% of cavernous angiomas are discovered without symptoms. This number is growing with increased use of MRI and genetic testing.

At least half of those with the Common CCM1 Mutation never have a symptom.

When to consider MRI or genetic testing

Focal seizures – uncontrolled movement in a limb or the face, smelling something that’s not there, staring.

Limb weakness, tingling, burning

Vision issues – double vision, jumpy vision, eye turning in, loss of part of visual field

Balance or coordination problems, dizziness that won’t stop

Facial paralysis that resembles Bell’s Palsy

Diaphragm spasms (resemble hiccups) that continue for extended period. This is an emergency.

Projectile vomiting, loss of consciousness are also emergencies.

General Symptoms That Overlap with Other Disorders

• Headache• Fatigue• Attention issues• Learning disability• Memory issues• Social skills deficits

New Lesion Formation

• People with the Common CCM1 Mutation will develop more lesions over time.

• Average rate is 0.4 new lesions/year, so average 64-year-old will have 24 lesions.

• But, there is wide variation not always reflected in symptoms. Some older adults have 1 lesion and some have hundreds.

Why be diagnosed? Actions that may help reduce risk

of hemorrhage

• Gut bacteria, may have a direct impact on the number of lesions that develop and, possibly, on how active the lesions are.

• It is important to protect the lining of the gut to prevent bad bacteria from entering the system.

• To do this, reduce or eliminate chemical preservatives and emulsifiers.

• Chemicals like polysorbate-80, mono- and diglycerides, and carrageenan can compromise the mucous lining, making it more likely that bad bacteria will enter the system.

Why be diagnosed? Actions that may help reduce risk

of hemorrhage

• Sleep apnea may have an impact on new lesion development.

• Mice with a CCM1 genetic mutation who were oxygen-deprived developed more lesions.

• In humans, this scenario is similar to sleep apnea.

• If there are symptoms of sleep apnea, it’s even more important for someone at risk for CCM1 to undergo a sleep study.

Why be diagnosed? Actions that may help reduce risk

of hemorrhage

• Vitamin D – make sure level is not low

• Cholesterol – not too high, but not too low (bad cholesterol)

• Weight – not too low• Stay away from blood

thinners like aspirin, unless benefit outweighs risk

• Reduce other controllable causes of inflammation, like smoking or flu

• Contact sports, roller coasters, hormonal birth control? Jury is out.

INFLAMMATORY INHIBITORS

NUTRITIONAL SUPPLEMENT

Pre-Clinical Phase One Phase Two Phase Three

Atorvastatin – Phase I/II enrolling

BA-1049

Lescol & Reclast

REC-994 (Tempol) – Phase I enrolling

Sulindac (Europe)

B-cell Depletion

Vitamin D3

Propranolol – EU Phase II Begins/ US Trial Seeking Funding

Gut Bacteria

Thrombospondin1

RHO KINASE INHIBITORS

SUPEROXIDE DISMUTASE

BETA BLOCKER

MICROBIOME

ANGIOGENESIS INHIBITOR

Access to Future Preventative Treatment

Genetic Testing: What to Consider

Benefits• Health monitoring for yourself and

your family• Early access to preventative

treatments• Reduce risk of misdiagnosis of

symptoms which can lead to wrong and possibly harmful treatments or no treatment. Especially important for children.

Genetic Testing: What to Consider

Considerations• Am I prepared to follow up with

medical monitoring? We can help connect you to the UNM CCM Center of Excellence and our peer support groups in Albuquerque and other areas.

• Am I prepared to talk to my family? Genetic counseling is available at UNM and elsewhere.

• Is there a potential for impact on other areas: life insurance, military service?

Determine Your Risk By Completing and Submitting a Bowtie Pedigree

Chart

Thank You!

We are grateful for the support of• Julian Grace Foundation• Angioma Alliance• Con Alma Health Foundation